Although England head coach Brian Ashton refuses to write off 36-year-old Regan from achieving further international honours, the writing is clearly on the wall.
Regan, labelled a "clown" by France coach Marc Lievremont following England's 24-13 victory over Les Bleus 11 days ago, makes way for an in-form Mears.
While Regan is currently battling to pin down a starting place with his club Bristol, Mears has played a prominent role maintaining Bath's healthy position in the Guinness Premiership title play-off zone.
The Edinburgh clash will be just Mears' fourth start during an England career that started against Samoa - the first of 18 appearances as a replacement - more than two years ago.
Mears said: "Ronnie [Regan's nickname] is a tough competitor, and I know he won't lie down.
"I have learnt a lot from him over the years, and the competitor in Ronnie is something I would like to have in my game."
Mears now has a chance to pin down the England number two shirt, and Ashton said: "It is a great opportunity for him.
"He has waited a long time, and I am sure he will take this opportunity with both hands.
"He's played extremely well for Bath this season. He has got a very rounded game, and we hope he will show it at the weekend.
"I don't think Mark Regan has recovered his World Cup form. He had a fantastic tournament, and was one of the motivating factors there in terms of going through to the final.
"I've had a very mature, frank conversation with him - he is a friend as well a player."
While Mears and Leicester flanker Tom Croft, who has been called up to replace ankle injury victim James Haskell, are the only changes from Paris up front, full-back Danny Cipriani could prove the headline act at Murrayfield.
The prodigiously-gifted Wasps prospect will become England's ninth full-back in 14 months since Ashton replaced Andy Robinson as head coach.
While Ashton freely admits full-back has proved a problem position for him during the last 20 Tests, Cipriani could stake long-term claims for England's number 15 shirt - starting this weekend.
Cipriani follows Iain Balshaw - the man he has replaced - Jason Robinson, Josh Lewsey, Olly Morgan, Mike Brown, Mark Cueto, Nick Abendanon and Mathew Tait into a troubled England role.
Cipriani said: "I am really looking forward to it - it is something I have always dreamt about.
"Full-back is where I first started my trade at Wasps, and Christian Cullen [the brilliant former New Zealand full-back] has always been my idol.
"He got me into rugby. I remember watching him on television playing for Wellington Hurricanes in the Super 12."
Cipriani, Wasps' current fly-half, last wore the number 15 shirt against Gloucester in an EDF Energy Cup clash four months ago.
Ashton, though, has no doubt about his ability to cope with whatever Six Nations wooden spoon candidates Scotland throw at him.
Ashton said: "Danny had a good season at 15 last year, playing extremely well in some big games.
"We are looking for a bit more solidity at the back, and it was always my intention to give him a start during this tournament."